As we expected, yesterday’s vaccine piece provoked a lot of discussion, almost all of it thoughtful and pertinent. Since we’ve already said we might be wrong, we thought we’d take some time to respond, using it as a way to keep thinking things through on our end. Writing is thinking and thinking is needed in this situation.

Over at FluTrackers.com (an excellent flu forum like Flu Wiki with highly informed people) there were a number of lengthy responses, most of them on the negative side. Since these folks follow events closely their opinions are also worth following closely. In addressing them I will also summarize the gist of yesterday’s post, which represents the Reveres’ joint opinion at this point.
1. We have been somewhat skeptical of the efficacy of influenza vaccination in the past. However reviewing the literature (we dealt with a good summary in this post recently) we have come to the conclusion that the vaccine works sufficiently that it is an important public health measure. Its efficacy varies but, depending upon the group, probably lies somewhere between 30% and 70%. In the case of a good match to a virus to which most of the population has no natural immunity, we believe 70% to be a good estimate considering the groups most at risk. This means that compared to an unvaccinated group, the vaccinated group will have 70% fewer infections. It means that 30% of those vaccinated who are exposed will still get the flu. Flu vaccine isn’t even close to 100% effective like DPT or MMR. But even 30% reduction in infection in a pandemic is a Big Deal in terms of demands on services, lost work time and productivity, pain and suffering, and of course, mortality, so we don’t think using the high end of efficacy makes much difference.

So that’s the first point that may separate us from others. We think the vaccine will work and we base that on experience with seasonal vaccine where numerous randomized clinical trials have been done (see the Basta-Halloran review we linked above; here it is again). Take a look at it and make up your own mind about this. If you don’t think the vaccine will work, then there’s no reason to get it. We think it will work (based on our review of the science) and that it will make a big difference to how well communities who use it sufficiently will get through whatever might come next.

2. Safety, adjuvanted or unadjuvanted. Yesterday’s post pointed out that it is not feasible to assure the advance safety of any product being consumed or administered to tens or hundreds of millions of people. No advance testing is possible for relatively rare adverse events that would still be numerous when that many people are exposed. But the mathematics of the adverse events versus the risks from flu, even if it is only the virulence of seasonal flu, is so overwhelmingly in favor of vaccination that we don’t think this is a hard call. True, there are various guesses that have to be made about how many people are infected, what the CFR will be, how well the vaccine will work, etc., and while we tried to be pretty conservative in most of them (we did use a high end number for vaccine efficacy because we thought the data for similarly placed populations merited it, but even if we’d used the lowest efficacy vaccines come out far ahead), and you might differ with some of them. At least you know what we assumed. But the major point is this. If you want to wait for assurances of safety, then you better have a definition of “safety” that is determinable ahead of time or you are just saying you won’t accept any vaccine. And for most of the rare events people talk about (e.g., Guillian-Barre Syndrome) there is no way to test for it in advance.

A related point was that there is no reason to trust vaccine manufacturers as they have a dismal record for honesty and probity. We agree and have complained bietterly about Big Pharma many times. But accepting this argument also means we reject essentially the entire modern pharmacopoeia since these folks also make all the other vaccines, antibiotics, hand sanitizers, etc., etc. We’ve argued frequently that influenza vaccines (and probably other vaccines) should be made by a regionalized network of international vaccine institutes outside the market system. We didn’t do that. So we are stuck with Big Pharma. It is what it is.

3. The adjuvant question. Two weighty objections to our advocacy of adjuvants have been advanced, one at FluTrackers and one by Jody Lanard here. They are slightly different but we will take them together. Vibrant62 at FluTrackers observes that the safety of adjuvants has been tested more often in the older age groups (where the immune response is more sluggish and adjuvants are more needed), not well tested in the young age groups. Vibrant62 suggests the decision doesn’t have to be “all or nothing” but we could use unadjuvanted vaccine for some age groups (or pregnant women) and adjuvanted vaccine for others. Let’s assume this is economically feasible (i.e., that two different vaccine could be made and distributed efficiently). If children and young adults really, on average, react quite differently to a particular adjuvant, then this will be seen in the safety and efficacy trials, unless it is rare, in which case we are in the same box we were earlier regarding trade-off with the benefit. There has been quite a lot of experience with adjuvants and influenza virus and also some with this particular virus. I will refer you to the excellent post by Vincent Racaniello at Virology Blog. Before giving my full answer to this, though, I want to address Jody Lanard’s objections, since my answer is the same to both.

Jody Lanard and Peter Sandman are among the most experienced and thoughtful practitioners of risk communication anywhere, so their views are of special significance. We usually agree, although not always. This seems to be one of the “not always” times. Jody’s concern has to do with how the US public will react to the idea that a relatively untested vaccine will contain an even more untested additive, especially after the 1976 swine flu debacle where it is widely reported that the vaccine was worse than the disease (although not reported that one reason this is so is that the disease never got out of Fort Dix so there was no disease averted by the vaccine). This comes at a time of high anxiety about vaccines among certain segments of the population, some of it sincere, much of it fed by paranoid conspiracy theorists who see monsters under every bed. The bad behavior of Big Pharma and the demonizing by the Far Right Noise Machine of any health measure promoted by government adds to the problem. The result is that the anti-vaxxer movement is killing and disabling children. The fear is that a government program with an adjuvanted vaccine will pour gasoline on this fire:

There is a great deal of undue — but thoroughly unmitigated — anti-vaccine feeling and fear in the U.S. The anti-vaccine activists and the vaccine-causes-autism activists are ready to roll with every flu vaccine Teachable Moment that comes along.

The more traction they can get by encouraging doubt and skepticism about flu vaccine among parents, the more children will end up unvaccinated against the “usual” childhood diseases.

So in the U.S., this is a really bad time to change the flu vaccine any more than necessary (a strain change is necessary, of course). (Jody Lanard in the Comment Thread of yesterday’s post)

In essence (and read the whole comment here), Dr. Lanard is saying it will backfire and make things worse. Instead of more people being vaccinated because of antigen sparing, fewer in the US will be vaccinated because parents will refuse the vaccine and it will have a spillover effect on other important childhood vaccination programs.

I understand this point of view and it comes from what I consider an authoritative source. But here’s where the question of “balance” that I discussed in yesterday’s post comes in. Jody and I have struck different balances on this. For us, the principal point of using adjuvant is to increase the number of people in the world who can be vaccinated, not just the number of people in the United States. Most of the viral antigen is made outside the US. We are rich so we bought it up and now less rich countries can’t get it. Our only entitlement to it is through the fact that the ability to live without influenza infection has become a commodity and the US has the means of exchange (money) to buy it. Adjuvants would make it more available to more people.

I am opposed to mandatory vaccination, even though I believe vaccination is an important public health measure that will save millions of lives. But there isn’t enough vaccine for everyone in the world, so if people in the US don’t want it, then any unused stock (keeping a small reserve) should be released by a date certain (say January 15 for the sake of argument) and given to others. I believe this will doom many Americans to severe sickness and some to a fatal illness, but the compensation is that many others, children and adults, in poorer parts of the world will be saved. Their lives are worth no less than American lives. If someone in this country, for whatever reasons, doesn’t wish to receive the vaccine, someone who wants it and needs it will be waiting.

There are real imponderables and trade-offs here with no easy answers. It is clear that our answer is not the same as others who have followed the issue as assiduously as we have and who have great expertise. That doesn’t make them right, or us right, or the US government’s position right. And different governments are making different decisions. We may never know what the right thing to do was because we will be dealing with a counterfactual: what would the world have been like if we’d done X instead of Y?

But the US is a big player in this high stakes game. It has ordered (and hence pre-empted for others) a lot of antigen, so it’s something worth discussing. So we’re discussing it.

Even if Dr. Mercola’s entire article made a single valid point regarding the use of adjuvants in the H1N1 vaccine, it is irrelevant to the US population. Based on poor science, packed with misinformation, and designed to promote unwarranted fear, his article is not a source of information, it is dangerous, irresponsible fear mongering.

The Canadian public health team is getting 50 million doses of adjuvanted H1N1 for our population (population of Canada: approx 30 million). Not mandatory, but there is sufficient fear here that the uptake is likely to be high.

The major issue with this is the adjuvanted version, due to extra safety testing, is unlikely to be available on such a scale until mid November. School has been back in action for two days already…. how long before the first outbreak?

I’m hoping if the uptake is lower than expected, they’ll do something similar to what you’re suggesting and release it to other nations. I thought the 50 million doses was both optimistic and a bit greedy.

I wish there was a way to convince hospital staff getting their shots was a good idea. Local surveys showed only about 15% of nurses got their annual flu shot. Hm… wonder who’s spreading the outbreaks? I’m a GP, and my whole office gets ours yearly.

The link to the above reference was in the French article I mentionned, as well as the initial Swedish study.

It also contained the transcript of a FDA hearing from February 2009, with Dr Vaughn (from GSK) saying:

“While there is a large safety experience with inactivated split influenza antigens in children 6 months of age and older, there is currently very limited pediatric safety experience using the ASO3 adjuvant. European regulatory authorities, as we heard this morning, have determined that these vaccines should be evaluated in children, including infants, and should include an evaluation of the effectiveness of boosting.”

Dr Vaughn initially describes ASO 3 by its full name “alpha-tocopherol-based adjuvant system number 3″ (related to vitamin E) before recognizing that it contains squalene when answering to a question by Dr Debold (FDA?).

Even if Dr. Mercola’s entire article made a single valid point regarding the use of adjuvants in the H1N1 vaccine, it is irrelevant to the US population. Based on poor science, packed with misinformation, and designed to promote unwarranted fear, his article is not a source of information, it is dangerous, irresponsible fear mongering.

Indeed. Dr. Mercola’s website is a wellspring of pseudoscience and quackery only marginally less nutty than Whale.to, which has been immortalized in Scopie’s Law. Maybe we should add a corollary to Scopie’s law to cover Mercola’s quacktastic website.

The path to a successful vaccine adjuvant – ‘The long and winding road.’
Derek T. O’Hagan and Ennio De Gregorio (both work for Novartis
Vaccines). Published in Drug Discovery Today 2009; Vol
14(11/12):541-551.

While you are all debating the benefits of an H1N1 vaccine, it has established itself in Atlanta and the Southeast quite nicely. Schools, colleges, and universities start in early-to-mid August here. H1N1 Cases have been confirmed at the University of Georgia, Emory University and Georgia Tech; hundreds of students at each school are affected (no one panicked, by the way). My daughter was in middle school for just 5 days when she and many of her fellow students were hit. She missed 5 days of school. A call to the pediatrician confirmed what I already figured – flu was rampant in kids; as long as the child is drinking/eating, keep her at home; antivirals would only be given to kids with pre-existing conditions. We weathered the illness and my husband and I remained healthy. We are in our mid-40’s, so I assume we have some immunity.

My question is, since we have been exposed, do we still need to get the H1N1 vaccine? I plan on us all getting the seasonal flu vaccine which is now becoming available through
my employer, a full month earlier than past years.

AtlantaKitchenParty: Being exposed is not the same as being infected (fortunately). So if you know you had it, then you don’t need the vaccine. You’ve been vaccinated naturally. But usually you don’t know, so in that case, I’d get it.

Someone with a latex allergy expressed their concern to me today about exposure to latex from the vaccine. I didn’t know what to say about that, so I poked around a little. As far as I can tell, GSK is the only manufacturer that uses latex in its process for the seasonal flu vax, so I’d assume that would hold for the pandemic vax as well, though I’m not sure. I also have no idea how much of the US supply is expected to come from GSK.

And there are no data on the use of adjuvanted flu vaccine in pregnant women – a fact that may add to the already high degree of reluctance many pregnant women feel about taking any medication or therapy.

“What is absolutely clear is that there is much more of a safety data base in pregnant woman with non-adjuvanted vaccine,” said Dr. Marie-Paule Kieny, head of the WHO’s vaccine research initiative, the division overseeing pandemic vaccine issues.

Revere, while I don’t disagree that it is impossible to ensure safety against rare adverse events when you are vaccinated millions of people, I’d like to suggest that the literature on the safety of adjuvant is both scanty and scary. I say this from having looked at the issue since 2005, some of the issues are (incompletely) written up as a series on Flu Wiki.

the results of Novartis’ GLP toxicology studies performed to fulfil global health authority requirements for clinical testing or product approvals have not been published, to date.

Lest you think they are generally shy about publishing, a cursory search on PubMed for MF59 returns 159 results.

Other issues: misleading/fraudulent references used to support safety, such as the use of a cosmetics review paper as the SOLE reference to support the safety of squalene. This reference was used in the IOM report on the safety of anthrax vaccine, as well as in A compendium of vaccine adjuvants and excipients compiled by scientists from the NIH and Walter Reed. There are a few strange things about this compendium: I downloaded it from the niaid site a while back, but it is no longer available online. All the links to the paper have stopped working. Also, the third (and last) author, Carl Alving of Walter Reed, listed on the document itself, is no longer listed as author on PubMed or anywhere else. Here are the relevant pages from the compendium showing the reference; check it out for yourself.

But these are just background. With regards to safety of adjuvanted flu vaccines, I can identify at least 3 major areas of concern:

1. the history and safety of MF59 and AS03 – while it’s been repeated everywhere that Fluad, the MF59 adjuvanted flu vaccine, is licensed in 20+ countries, what most people do not know is that it was licensed initially (ie went through regulatory scrutiny) in Italy, a country whose governance is shall we say probably not up to the highest or most honest standards. It was then approved automatically in the rest of the EU through Mutual Recognition Agreement (more here and here)

Fluad is licensed for use in those >65, since 1997. While Novartis throws around numbers and claim (depending on the source) anywhere between 20-40 million doses have been distributed, no information is available as to how often this vaccine is used off-label for non-elderly subjects. Why is this important? Because their own review (Schultze, link above) says that in post-marketing surveillance, 34% of reported adverse events were from non-elderly adults. Now, it may be that non-elderly people were more likely to report AEs, and I’m not an epidemiologist, but personally, that looks like a suspiciously high number to me. Is that a red flag? You tell me.

There is even less information on the safety of AS03, the adjuvant used by GSK in their pandemic vaccine. What limited information there is, is both hard to find and disturbing. For example, in the ‘mock-up’ dossier that they filed with the EMEA, for an H5N1 pandemic vaccine, those who received the adjuvanted vaccine reported 50% more ‘medically significant’ adverse events (as determined by GSK but criteria unknown) compared to controls who received the regular seasonal vaccine.

Another example, in one pediatric clinical trial with only 300 kids receiving the adjuvanted vaccine, there was one case of autoimmune hepatitis. (Source: FDA meeting, Feb 19, 2009) Another adult case was recently reported in a H1N1 workshop summary for the National Biodefense Science Board. In both instances, little information is available except nonspecific reassurances from the GSK representative, who, btw also stated that “there is no biological plausibility” of autoimmune reactions or adjuvants having effects beyond the muscle and lymph node, an incredible statement given that the vaccine is given at the muscle for the purpose of producing immunological protection against a virus that attacks the lungs. As I wrote in this summary of issues around Mass Vaccination against Swine Flu H1N1 in the US, the ‘biological possibility’ of adjuvant-induced autoimmune disease is amply demonstrated in decades of use of such adjuvants to induce autoimmune diseases in animal models, or as shown in this list of >4,000 peer-reviewed journal articles on the subject.

2. regulatory issues – Adjuvants are by design potent immunoactive substances. Do we have ways of detecting excessive immunostimulation? Right now, in the absence of animal models (see FDA comment below) the bulk of safety signals is supposed to come from AEs reported either in clinical trials – where the trial sizes eg for EMEA approval in the EU, is only sufficient to detect AEs that occur at 1% of vaccinations, see Swine Flu Vaccine in 5 Days? – or post-marketing surveillance, in this case after we vaccinate millions and millions. Conceptually, the issue is this: While we have correlates of protection, in the form of HI antibody titers, to show immunogenicity, we do not have similar sub-clinical markers for correlates of excessive or abnormal immune stimulation, so we won’t know if someone is having problems with excessive immune modulation until they develop disease AND if they report it.

However, let me point out that post-marketing surveillance is dependent on demonstration of clear temporal relationship between vaccination and the AE, but this may not be possible for more chronic, delayed onset consequences such as autoimmune diseases. The FDA is well aware of this – in fact, they co-hosted a meeting last December with the NIAID, Adjuvants and Adjuvanted Preventative and Therapeutic Vaccines for Infectious Disease Indications (transcripts at link) to thrash out the many unresolved questions. Suffice it to say that the issues remain unresolved. Here are a couple of quotes from Jesse Goodman, now the (acting?) Chief Medical Officer of the FDA, in that meeting, ie as recently as December 2008:

So at FDA, we are asked to make some difficult judgments ranging from clinical trial judgments to approval judgments to where to put resources in terms of trying to stimulate product development. And it comes down to, in this area, enhanced immunity versus inflammation, adverse events, and potentially autoimmunity.

also:

The toxicology of vaccines, not to mention the toxicology of adjuvants has been a really neglected area. And, you know, we’ve tended to only recently pay attention to this. And we’ve had just tools of conventional toxicology, which largely focus on drug effects on organs. And, of course, when you are talking about immunotoxicology, there are not a lot of good models. I think there is a huge opportunity for the scientific community to develop better nonclinical or non-human models and even human studies that could tell us about the safety of novel vaccines and adjuvants.

The issue of immunotoxicity is only recently receiving some attention; the first ICH Guideline for Immunotoxicity Studies for Human Pharmaceuticals were only released in 2005, and the first iteration only deals with immunosuppression by pharmaceuticals. The work on detection of excessive immunostimulation is still out in the future…

3. parallel biological mechanisms in adjuvanticity and autoimmunity – I have already mentioned that for decades, adjuvants similar to MF59 and AS03 were/are used in animal models to induce autoimmune diseases such as experimental autoimmmune encephalomyelitis or EAE, the animal model for multiple sclerosis.

Briefly, in the case of vaccines, the fundamental issue is that adjuvanted vaccines induce strong local inflammatory reactions. This is part and parcel of their adjuvanticity, but inflammation also results in tissue destruction and cell necrosis, causing exposure of intracellular antigens to the immune system. In the steady state (ie in the absence of inflammation), small amounts of autoantigen are not immunogenic but instead induce/promote tolerance. But inflammation and necrosis provide the necessary ‘co-stimulatory signal’ for activation of an immunogenic response to these autoantigen instead.

More biological mechanisms were discussed at the FDA/NIAID adjuvant meeting eg the importance of peripheral (as opposed to central) tolerance, such that local reactogenicity can have an impact on regulatory T cell function. One interesting confluence of science lies in the finding, reported in this 1994 paper from Chiron (before it became Novartis) Valensi et al that MF59-adjuvanted flu vaccine induced high serum levels of IL6. Immunology has advanced a lot since then, and we now know that IL6 is a necessary and potent trigger (Blanco 2008, Romagnani 2008) for a type of immune response (Th17) associated with autoimmune diseases. In fact, regulatory T cells that normally suppress autoreactive responses, may, in the presence of high levels of IL6, lose their suppressive function and switch to Th17 response instead. (Xu 2007, Kitani 2008)

I’m no immunologists, but these are just a few examples of a vast amount of information each of which on its own may not be conclusive, but together IMHO gives sufficient warning for us to treat adjuvants with a lot of respect, and scrutiny. I’m not opposed to them in principle; I recognize that there are good reasons for adjuvant use, but the state of our science is such that we really do not yet have the tools that match their potency. Many fundamental questions remain unanswered, eg adjuvants induce antibody levels that are sometmies hundreds or even thousands of times higher than what is required. Do we really NEED such strong responses to be protective? There are plenty of reasons to think, more is not better.

Apologies for such a long post, but this issue is important if only because, at the end of the day, commercial adjuvants are proprietary products. Everything about them are closely held secrets, such that in the absence of good regulatory protocols, we as consumers are simply asked to take the manufacturer’s word on faith. The bottomline is, how much do you trust vaccine companies to look after the longterm safety of the public? I must say that what I have seen, in coming up close and observing these people in meetings, leaves me increasingly cynical and cautious…

There’s one important point I missed out, in the above long comment, and that is the issue of genetic susceptibility. Genes play a part in autoimmune diseases, but not everyone with the genes will develop disease in their lifetime. The concordance rate (ie the odds of a second twin getting a disease if the first twin has it) varies approx between 15-70%, depending on disease. (See table for a number of diseases here.)

Turn it the other way round, it also means that we have in our population an unknown but possibly sizeable subgroup with the genetic predisposition who are not destined to develop disease if they are not exposed to the right triggers. Vaccine adjuvants can, at least theoretically, trigger some nasty diseases in a heck of a lot of people who may otherwise remain healthy…

I wonder what psycho-somatic syndrome will be blamed on the H1N1 vaccine? Once you hear of a sudden development of a “syndrome” related to the use of the vaccine,together with a class action lawsuit, it will be a cardinal sign that the pandemic is over.

How about coughing up blood after trialing an adjuvanted swine flu vaccine in Germany? Of course, the people running the trial say it was a coincidence. (Since they couldn’t write a side effect like that off to being psychosomatic.)

Regarding Americans donating their antigen and using an adjuvant, there is not just a “we” in this country that is rich. Many of us are struggling and have no insurance, or merely the illusion of health insurance. (The reality to be faced should we ever need that insurance.)

If injured by a vaccine, we will face the pervasive attitude and morality expressed so well by chbweber. We will be cut from the herd very quickly like this young lady was.

The only thing most people would agree about is the unpredictability of autoimmune reactions to vaccines, drugs, or viral infections themselves. The reason that is true is the same reason you should not be asking Americans to give away the antigen that was bought with their tax dollars. Little research is done in this field because it is not profitable, just as it is not profitable to care for those people that are injured by vaccines.

If that is the way that it is in this country, who wants to be the public servant blamed for experiences like that reported by the German vaccine tester, or worse outcomes? At least with a vaccine most like current flu vaccine technology, perhaps characteristics of the pandemic H1N1 virus itself will be blamed for adverse outcomes after vaccination, and the vaccinated population will have the same number or less of these adverse outcomes as those unvaccinated who contract that flu.

Those are the stats that you want to see if you support vaccination. The stats could be even better some day if research into individual immunity were done.

On Sept 8, 2009, Dr. redrabbitslife’s last comment “I wish there was a way to convince hospital staff getting their shots was a good idea. Local surveys showed only about 15% of nurses got their annual flu shot. Hm… wonder who’s spreading the outbreaks?…..” Perhaps a group of epidemiologists could look at the Rush experience (Rush University Medical Center, Chicago, IL, USA) after this year since this year (first time) it is a mandate that all employees in every capacity – including consultants etc – must have both the seasonal flu vaccine and the H1N1 vaccine when it is available. The hospital is providing both free to all staff, including the latex free and Thimerisol free versions. I think it would be interesting to collect some data from this group and review it and see if anything can be learned from it.

The real reason that they’ve stopped testing for swine flu is that a very large proportion of tests of flu-like symptoms proved not to be H1N1.

In fact in 80% of tests there was no flu ANY strain whatsoever. Rhinovirus gets some bad press of late.

So why would any sensible person risk being jabbed with stuff which the manufacturer admits in print on the packet has a 1 in 10,000 chance of inducing Guillain-Barre. G-B results in death-like symptoms including a fairly comprehensive total-paralysis

Trust me, I’m an architect. Joking aside, a naturopath-minded architect’s advice might be a whole lot better for your health than the misleading info you often risk from your Board-certified MD…

…unless she is one of those rare allopaths who actually read and translate the horrendous warnings on your product insert… AND has the wisdom to bin the batch.

No need to ask her to prescribe nanosilver and garlic. You can buy both online without leaving home.